WO2023115593A1 - Comprimé d'apixaban et son procédé de préparation - Google Patents

Comprimé d'apixaban et son procédé de préparation Download PDF

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Publication number
WO2023115593A1
WO2023115593A1 PCT/CN2021/141416 CN2021141416W WO2023115593A1 WO 2023115593 A1 WO2023115593 A1 WO 2023115593A1 CN 2021141416 W CN2021141416 W CN 2021141416W WO 2023115593 A1 WO2023115593 A1 WO 2023115593A1
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WO
WIPO (PCT)
Prior art keywords
apixaban
prescribed amount
tablets
granulation
mix
Prior art date
Application number
PCT/CN2021/141416
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English (en)
Chinese (zh)
Inventor
袁承烨
马晶
陆鹏
项燕飞
Original Assignee
浙江海正药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by 浙江海正药业股份有限公司 filed Critical 浙江海正药业股份有限公司
Priority to PCT/CN2021/141416 priority Critical patent/WO2023115593A1/fr
Publication of WO2023115593A1 publication Critical patent/WO2023115593A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a tablet of apixaban and a preparation method thereof.
  • Cardiovascular and cerebrovascular diseases have seriously threatened human health due to their high incidence, high recurrence rate, high disability rate and high mortality rate.
  • the incidence of cardiovascular and cerebrovascular diseases in my country is increasing year by year.
  • Thrombosis is a common vascular disease caused by narrowing of vascular lumen, blood embolism and occlusion of circulatory system.
  • Antithrombotic drugs can be divided into three types according to their mechanism of action: antiplatelet drugs, anticoagulant drugs, and thrombolytic drugs.
  • Apixaban is a new type of oral anticoagulant. US6967208 first described that apixaban has the function of coagulation factor Xa inhibitor, and it is developed as an oral administration for various indications that require the use of antithrombotic drugs. medicine way.
  • Apixaban is a novel oral selective inhibitor of activated factor Xa, chemical name: 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7- Oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-C]pyridine-3-carboxamide, the molecular formula is C 25 H 25 N 5 O 4 , its structural formula is as follows:
  • apixaban Under all physiological pH conditions, apixaban has poor water solubility and low in vitro dissolution rate, which affects the bioavailability of the drug.
  • the conventional method is to add a large amount of surfactant in the prescription, but this method will bring corresponding toxic and side effects to the human body when increasing the dissolution rate of the drug. Therefore, it is very important to find a safe method to increase the dissolution rate of apixaban and improve the absorption of apixaban.
  • the invention provides an apixaban tablet with good dissolution rate and high bioavailability.
  • the apixaban tablet comprises the following components: apixaban bulk drug, water-soluble carrier material, carrier, filler and lubricant.
  • the specification of the apixaban tablet is 2.5 mg.
  • the present invention also provides a preparation method of Apixaban tablets, the steps are as follows:
  • step (3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 140-160rpm, the cutter is 1800-2200rpm, and the granulation is 8-12 minutes ;
  • step (3) Pass the granules obtained in step (3) through a 20-mesh sieve, cool to room temperature, then carry out dry sizing, and pass through a 20-mesh sieve;
  • step (4) Mix the granules obtained in step (4) with the lactose monohydrate and microcrystalline cellulose of the prescribed amount;
  • the steps are as follows:
  • step (2) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 150rpm, the cutter is 2000rpm, and the granulation is 10 minutes;
  • step (3) Pass the granules obtained in step (3) through a 20-mesh sieve, cool to room temperature, then carry out dry sizing, and pass through a 20-mesh sieve;
  • the present invention utilizes solid dispersion technology to make apixaban and polyethylene glycol form a colloidal solution, improve drug dissolution rate and solubility, increase drug absorption, and improve bioavailability.
  • the present invention adopts crospovidone as the carrier of the above-mentioned colloidal solution, utilizes the characteristics of its large specific surface area, granules the colloidal solution after being evenly adsorbed on crospovidone, and further improves dissolution rate and solubility.
  • Figure 1 shows the apixaban tablets and commercially available Eliquis in Example 7 In vitro dissolution test results chart
  • This example provides the prescription (Table 1) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):
  • step (3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation. Stirring paddle 150rpm, cutter 2000rpm. Granulate for 10 minutes.
  • step (3) Pass the granules obtained in step (3) through a 20-mesh sieve, and cool to room temperature. Carry out dry granulation again, cross 20 mesh sieves.
  • step (5) Mix the granules obtained in step (4) with the prescribed amount of lactose monohydrate and microcrystalline cellulose evenly.
  • This example provides the prescription (Table 2) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):
  • step (3) The granules obtained in step (3) are passed through a 20-mesh sieve, cooled to room temperature, then dry sized, and passed through a 20-mesh sieve.
  • step (5) Mix the granules obtained in step (4) with the prescribed amount of lactose monohydrate and microcrystalline cellulose evenly.
  • This example provides the prescription (Table 3) and preparation process for preparing 8000 Apixaban tablets (specification 2.5 mg/tablet):
  • step (5) Mix the granules obtained in step (4) with the prescribed amount of lactose monohydrate and microcrystalline cellulose evenly.
  • step (6) Mix the mixed granules obtained in step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to obtain Apixaban tablets.
  • This example provides the prescription (Table 4) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):
  • step (5) Mix the granules obtained in step (4) with the prescribed amount of lactose monohydrate and microcrystalline cellulose evenly.
  • step (6) Mix the mixed granules obtained in step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to prepare apixaban tablets.
  • This example provides the prescription (Table 5) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):
  • step (6) Mix the mixed granules obtained in step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to prepare apixaban tablets.
  • step (3) Add the slurry in step (2) to the mixed powder in step (1) to granulate, the rotation speed of the stirring blade is 150rpm, and the cutter is 3000rpm.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un comprimé d'apixaban et son procédé de préparation. Un matériau polymère hydrophile est introduit dans une prescription en tant que support soluble dans l'eau. L'apixaban et le matériau polymère hydrophile sont mélangés puis soumis à une granulation par fusion à chaud pour former une dispersion solide. Le problème de la faible solubilité in vitro des comprimés d'apixaban est efficacement résolu sans ajout d'un tensio-actif. Le procédé de granulation par fusion à chaud est simple, a une bonne reproductibilité, et peut être facilement industrialisé.
PCT/CN2021/141416 2021-12-26 2021-12-26 Comprimé d'apixaban et son procédé de préparation WO2023115593A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/141416 WO2023115593A1 (fr) 2021-12-26 2021-12-26 Comprimé d'apixaban et son procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/141416 WO2023115593A1 (fr) 2021-12-26 2021-12-26 Comprimé d'apixaban et son procédé de préparation

Publications (1)

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WO2023115593A1 true WO2023115593A1 (fr) 2023-06-29

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102908324A (zh) * 2012-10-31 2013-02-06 南京正科制药有限公司 一种阿哌沙班片
CN103830199A (zh) * 2014-03-24 2014-06-04 重庆东得医药科技有限公司 含阿哌沙班的药用制剂及其制备方法
WO2015121472A1 (fr) * 2014-02-17 2015-08-20 Sandoz Ag Composition pharmaceutique contenant de l'apixaban
WO2017163170A1 (fr) * 2016-03-21 2017-09-28 Sun Pharmaceutical Industries Limited Composition pharmaceutique comprenant de l'apixaban
EP3243505A1 (fr) * 2016-05-13 2017-11-15 Zaklady Farmaceutyczne Polpharma SA Composition pharmaceutique comprenant de l'apixaban amorphe
CN108096205A (zh) * 2018-02-27 2018-06-01 南京正科医药股份有限公司 一种阿哌沙班片及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102908324A (zh) * 2012-10-31 2013-02-06 南京正科制药有限公司 一种阿哌沙班片
WO2015121472A1 (fr) * 2014-02-17 2015-08-20 Sandoz Ag Composition pharmaceutique contenant de l'apixaban
CN103830199A (zh) * 2014-03-24 2014-06-04 重庆东得医药科技有限公司 含阿哌沙班的药用制剂及其制备方法
WO2017163170A1 (fr) * 2016-03-21 2017-09-28 Sun Pharmaceutical Industries Limited Composition pharmaceutique comprenant de l'apixaban
EP3243505A1 (fr) * 2016-05-13 2017-11-15 Zaklady Farmaceutyczne Polpharma SA Composition pharmaceutique comprenant de l'apixaban amorphe
CN108096205A (zh) * 2018-02-27 2018-06-01 南京正科医药股份有限公司 一种阿哌沙班片及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUAN, ZHIYU: "Excipients and Packaging Materials Used for Drug Formulation", 31 January 2017, CHINA MEDICAL SCIENCE AND TECHNOLOGY PRESS , CN , ISBN: 978-7-5067-8768-0, article GUAN, ZHIYU: "Lubricants", pages: 86 - 89, XP009547396 *

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